Stroke is the third leading cause of death in the United States and a major cause of serious, long-term disability. Understanding the mechanisms that underlie stroke and the development of new therapeutic strategies is of key importance and is the long-term objective of this study. Much experimental evidence points to a beneficial action of angiotensin II type 2 receptors (AT2R) in stroke that is enhanced in the presence of Ang II type 1 receptor (AT1R) blockers (ARBs), drugs that are effective anti-stroke agents. Thus, we have developed the general hypothesis that neuronal over expression of AT2R in the cerebral cortical and striatal regions will provide protection during ischemic stroke. In addition, we hypothesize that the combination of AT2R over expression and ARB administration will provide additional cerebroprotection than either alone. Specifically, we hypothesize that viral-mediated delivery of the AT2R gene and consequent neuronal over expression of AT2R within the cortical and striatal regions will reduce the infarct size and neurological deficits resulting from experimentally induced stroke. We further hypothesize that viral mediated delivery of an AT2R shRNA and consequent reduction in AT2R expression will exacerbate the neurological deficits and increase infarct size. The goal of this proposal is to test these hypotheses, using a combination of gene transfer, molecular, cellular and in vivo experimental approaches. The data from this study will not only help to solidify a cerebroprotective role of AT2R in stroke, but will help to determine whether the over expression of AT2R in the CMS can elicit a beneficial action. The specific aims are: (1) Characterize viral-mediated over expression and reduction of AT2R in rat cerebral cortical and striatal regions. (2)Determine whether viral-mediated neuronal over expression of AT2R elicits cerebroprotection during ischemic stroke and improves the cerebroprotective action of ARBs. (3)Determine whether viralmediated reduction of neuronal AT2R potentiates the neural damage elicited by ischemic stroke and reduces the cerebroprotective action of ARBs. In summary, the experiments proposed here will not only allow us to solidify a cerebroprotective role of AT2R in stroke, but will also allow us to determine whether over expression of AT2R in the CNS can provide a beneficial action alone or in in combination with ARBs. PUBLIC HEALTH RELEVANCE: These studies are relevant to public health as they will help to understand what happens in the brain after a stroke occurs, and may identify a new therapeutic target that would be helpful in reducing stroke symptoms. This is clearly relevant to the mission of the National Institutes of Neurological Disorders and Stroke.